Evaluation of the Reference Tissue Models for PET and SPECT Benzodiazepine Binding Parameters

doi:10.1006/nimg.2002.1233

NeuroImage

Volume 17, Issue 2, October 2002, Pages 928-942

https://doi.org/10.1006/nimg.2002.1233 Get rights and content

Abstract

Recently, reference tissue methods have been proposed to estimate binding potential from PET data. A reference region without specifically bound ligand is used as an indirect input function to enable the expression of the time–concentration curve of a region of interest using a compartment model. However, PET dopaminergic and serotoninergic studies have shown differences between binding potential (BP) values obtained with reference tissue methods and those obtained with conventional kinetic modeling using an arterial input function. In this study, we measured the BP values for the benzodiazepine receptors in seven subjects using PET [¹¹C]flumazenil and SPECT [¹²³I]iomazenil radioligands. We compared the BP values obtained using the reference tissue methods with those obtained using the conventional kinetic method. These values were also compared with the absolute value of receptor density, B_max^′. For the PET studies, a multi-injection approach employing labeled and unlabeled flumazenil was used to estimate the main binding parameters, BP and B_max^′. For SPECT studies, a single injection protocol of [¹²³I]iomazenil was used to estimate BP values. The BP values were estimated using one- and two-tissue compartment models for the target region. Similar BP values were obtained using either the one- or two-tissue compartment model. This is probably due to the rapid equilibrium between tissue compartments reached with these radioligands. For PET and SPECT, these BP values were highly correlated (r > 0.960) to the BP values obtained using the arterial input function. We also found high correlations between the BP values obtained using the simplified reference tissue method and the receptor density parameter B_max^′ (r > 0.884). However, the reference tissue methods yielded lower BP values than those obtained using the conventional approach. Moreover, there was a bias on BP values that was not a simple scaling. It seems that the physiological values found in gray matter structures using these radioligands give acceptable BP values. We conclude that the reference tissue methods should be carefully evaluated for each radioligand.

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Therefore, an effect of isoflurane could be expected in GABAA receptors of all animals, which should not interfere in group comparisons. While the pons is a well-accepted reference tissue, it is not entirely devoid of GABAA receptors [44–46]. In fact, no brain regions can be considered completely GABAA receptor free [25,26].
[¹¹C]Flumazenil is a well–known PET tracer for GABA_A receptors and is mainly used as an imaging biomarker for neuronal loss. Recently, GABA_A receptors on immune cells have been investigated as target for modulation of inflammation. Since neuronal loss is often accompanied by neuroinflammation, PET imaging with [¹¹C]flumazenil is potentially affected by infiltrating immune cells. This may also compromise the validity of using the pons as reference tissue in quantitative pharmacokinetic analysis. This study aims to evaluate whether inflammatory processes in the brain can influence [¹¹C]flumazenil uptake and affect the outcome of pharmacokinetic modeling when the pons is used as reference tissue.
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The mutli-injection approach can be considered a “gold-standard” in modeling radiotracer kinetics in the brain, permitting an in-depth decomposition of the radioactive signal and full quantification of kinetic parameters, to our knowledge more than any other approach. Its use to validate simpler quantitative methods is invaluable (Dumas et al., 2015; Millet et al., 2002, 2000a, 2006, 2012). However, the estimation of a high number of parameters through a very complex protocol naturally comes at a cost.
Molecular imaging of the D_2/3 receptor is widely used in neuropsychiatric research. Non-displaceable binding potential (BP_ND) is a very popular quantitative index, defined as the product of the receptor concentration (B_avail) and the radiotracer affinity for the receptor (1/appK_d). As the appK_d is influenced by parameters such as the endogenous neurotransmitter dynamics, it often constitutes a confounding factor in research studies. A simplified method for absolute quantification of both these parameters would be of great interest in this context. Here, we describe the use of a partial saturation protocol that permits to produce an in vivo Scatchard plot and thus estimate B_avail and appK_d separately_, through a single dynamic SPECT session. To validate this approach, a multi-injection protocol is used for the full kinetic modeling of [¹²³I]IBZM using a 3-tissue compartment, 7-parameter model (3T-7k). Finally, more “classic” BP_ND estimation methods are also validated against the results of the 3T-7k.
Twenty-nine male rats were used. Binding parameters were estimated using the 3T-7k in a multi-injection protocol. A partial saturation protocol was applied at the region- and voxel-level and results were compared to those obtained with the 3T-7k model. The partial saturation protocol was applied after an adenovirus-mediated D₂ receptor striatal overexpression and in an amphetamine-induced dopamine release paradigm. The Simplified Reference Tissue Model (SRTM), the Logan's non-invasive graphical analysis (LNIGA) and a simple standardized uptake ratio (SUR) method were equally applied.
The partial saturation experiments gave similar values as the 3T-7k both at the regional and voxel-level. After adenoviral-mediated D₂-receptor overexpression, an increase in B_avail by approximately 18% was observed in the striatum. After amphetamine administration, a 16.93% decrease in B_avail (p<0.05) and a 39.12% increase (p<0.01) in appK_d was observed. BP_ND derived from SRTM, LNIGA and SUR correlated well with the B_avail values from the 3T-7k (r=0.84, r=0.84 and r=0.83, respectively, p<0.0001 for all correlations).
A partial saturation protocol permits the non-invasive and time-efficient estimation of B_avail and appK_d separately. Given the different biological phenomena that underlie these parameters, this method may be applied for the in-depth study of the dopaminergic system in translational molecular imaging studies. It can detect the biological variations in these parameters, dissociating the variations in receptor density (B_avail) from affinity (1/appK_d), which reflects the interactions of the receptor with its endogenous ligand.
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The partial saturation approach (PSA) is a simple, single injection experimental protocol that will estimate both B_avail and appK_D without the use of blood sampling. This makes it ideal for use in longitudinal studies of neurodegenerative diseases in the rodent. The aim of this study was to increase the range and applicability of the PSA by developing a data driven strategy for determining reliable regional estimates of receptor density (B_avail) and in vivo affinity (1/appK_D), and validate the strategy using a simulation model.
The data driven method uses a time window guided by the dynamic equilibrium state of the system as opposed to using a static time window. To test the method, simulations of partial saturation experiments were generated and validated against experimental data. The experimental conditions simulated included a range of receptor occupancy levels and three different B_avail and appK_D values to mimic diseases states. Also the effect of using a reference region and typical PET noise on the stability and accuracy of the estimates was investigated.
The investigations showed that the parameter estimates in a simulated healthy mouse, using the data driven method were within 10 ± 30% of the simulated input for the range of occupancy levels simulated. Throughout all experimental conditions simulated, the accuracy and robustness of the estimates using the data driven method were much improved upon the typical method of using a static time window, especially at low receptor occupancy levels. Introducing a reference region caused a bias of approximately 10% over the range of occupancy levels.
Based on extensive simulated experimental conditions, it was shown the data driven method provides accurate and precise estimates of B_avail and appK_D for a broader range of conditions compared to the original method.
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2014, Nuclear Medicine and Biology
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Obviously, performing scans of minimal duration, employing a model that requires no blood sampling and yet obtaining accurate parameters is a critical factor for the success of clinical and preclinical experiments. All these questions have been thoroughly assessed in human and other primate studies regarding kinetic, graphical and equilibrium analyses [7,20,22,23,33,40–42]. Nevertheless, no study on rodent GABAA quantification with SPECT exists.
In vivo imaging of GABA_A receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [¹²³I]Iomazenil, an antagonist of the GABA_A receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained.
Five male Sprague–Dawley rats were used for [¹²³I]Iomazenil brain SPECT scans. Binding parameters were obtained with a one-tissue compartment model (1TC), a constrained two-tissue compartment model (2TC_c), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed-activity images. In addition, we employed factor analysis (FA) to deal with noise in data.
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¹: To whom correspondence and reprint requests should be addressed at Hopitaux Universitaires de Genève, Unité de Neuroimagerie Psychiatrique, 2 chemin du Petit-Bel-Air CH-1225 Chêne-Bourg, Genève, Suisse. Fax: (41 22) 305 53 75. E-mail: [email protected].

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Regular ArticleEvaluation of the Reference Tissue Models for PET and SPECT Benzodiazepine Binding Parameters

Abstract

Eur. J. Pharmacol.

Neurosci. Lett.

Life Sci.

Nucl. Med. Biol.

Neuroscience

Neuroscience

NeuroImage

NeuroImage

Nucl. Med. Biol.

Lancet

Nucl. Med. Biol.

Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil

J. Nucl. Med.

SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil: Kinetic and equilibrium paradigms

J. Nucl. Med.

Release of acetylcholine and GABA, and activity of their synthesizing enzymes in the rat pontine reticular formation

Neurochem. Res.

Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol

J. Cereb. Blood Flow Metab.

Concept of reaction volume in the in vivo ligand-receptor model [see comments]

J. Nucl. Med.

Role and origin of the GABAergic innervation of dorsal raphe serotonergic neurons

J. Neurosci.

Positron emission tomography compartmental models

J. Cereb. Blood Flow Metab.

Quantitation of carbon-11-labeled raclopride in rat striatum using positron emission tomography

Synapse

Relationship of flumazenil and glucose PET abnormalities to neocortical epilepsy surgery outcome

Neurology

Regular Article
Evaluation of the Reference Tissue Models for PET and SPECT Benzodiazepine Binding Parameters